The report on the NIH RAC meeting discussing the death of the patient
during a clinical trial of an AAV vector has been published, and can be
found in the link below. Links are also provided to comments on the case
which were recently published in Nature and Nature Medicine. In one of the
articles, doctors and scientists are quoted who criticize the design of
the trial.AAV death poor trial
designAAV death RAC meetingAAV death therapy on
trialNature comment

Update
on death of patient in AAV-vector trial

It has been revealed that the patient who recently died while taking
part in a clinical trial of an AAV vector-based anti-arthritis treatment
was infected with a fungus that usually causes only a mild illness and a
cold-sore virus which is normally kept in check by the immune system, but
which had both spread throughout her body, suggesting that her immune
system was seriously impaired. This may be related, however, to the fact
that she was also taking conventional immune-suppressing drugs for her
arthritis. A link to the news item, and a recent article in Science about
the case can be found below:
washingtonpost.com
article in Science

New
setbacks in gene therapy trials

Two further adverse events in gene therapy clinical trials have recently
been reported.

A patient in the clinical phase I trial to treat X-SCID sufferers
performed at the Necker hospital in Paris has developed a leukemia-like
disease, about 5 years following treatment. This is the fourth patient to
develop such a condition in this trial, and means that half of the
patients who were successfully treated have gone on to experience this
adverse side-effect. However, in a similar trial performed in London, no
adverse events have yet been observed, indicating that protocol-specific
differences in the trials may be critical determinants in the genotoxicity
profile of this therapy.

In an unrelated clinical trial, using an AAV vector to treat arthritis, a
patient died in a clinical trial following a second administration of the
vector, which was designed to express Tumor Necrosis Factor Receptor. This
trial has been placed on hold, and all related trials involving AAV
vectors are being investigated by the FDA. The cause of death of the
patient has as yet not been established, however, and hence it is not
known if it was related to the gene therapy. Links to the FDA statement
and news items can be found below:

In April of this year, Niels-Bjarne Woods et
al. published a brief communication in Nature (link
to Woods et al. pdf), where they presented data which they claimed
demonstrated that the therapeutic gene used to treat X-SCID in human gene
therapy trials (IL2RG) is oncogenic when overexpressed via a lentiviral
vector in a murine model of X-SCID. This is an important finding, since
three out of a total of 20 human patients treated with this gene (albeit
using a retroviral vector) developed clonal T-cell leukemia. Arising from
this publication, two further articles appeared in Nature in September of
this year, both of which challenge the findings of Woods et al.. Karin
Pike-Overzet et al. (link to
Pike-Overzet et al. pdf) find that overexpression of the IL2RG gene
does not affect T-cell development, and propose that it is not directly
oncogenic, but that it its overexpression could contribute indirectly to
oncogenesis by allowing the normal progression of T-cell development that
are permissive for the pro-leukemic effects of genuine oncogenes such as
LMO2. Thrasher et al. also present the results of experiments in which
human IL2RG was expressed in mice and in which none of the animals
developed tumours. Both Pike-Overzet et al. and Thrasher et al. also argue
that there are fundamental differences in the T-cell development between
mice and humans, and that care must be taken in attempting to extrapolate
the results of murine studies to having relevance in a human setting. In
the same issue, Woods et al. reply to both of these criticisms,
emphasizing that their intention was only to warn that IL2RG, when
overexpressed in some settings, has the potential to be oncogenic, and
that their results should in no way stimulate drastic changes in currently
successful gene therapy protocols. Their major point remains, however,
that the expression of IL2RG (and, by extrapolation of all transgenes)
used in gene therapy should, if possible, not exceed physiological levels.

Related to this debate, Shou et al. recently published an article (link
to Shou et al. pdf) investigating the risk factors for insertional
mutagenesis in a mouse model of X-SCID gene therapy, and Buchholz and
Cichutek (link to Buchholz et al. pdf)
published a commentary dedicated to the ongoing debate as to whether
clinical trials should still go ahead using conventional retroviral
vectors, or whether the use of self-inactivating (SIN) vectors should
become standard)

Finally, a second publication from the Thrasher group documents the
successful gene therapy of ADA-SCID (link
to Gaspar et al. pdf).

Report
on the Life Sciences 2006 meeting

The ANGT took part in the
annual meeting in Salzburg from September 25th to 27th, along with the
other Austrian societies representing the Life Sciences.

The Gene Therapy session was a
resounding success, with a blend of established, internationally renowned
scientists and young home-grown talent providing insights into various
aspects of gene therapy from the research bench to clinical application.

The session was opened with
the Austrianova Gene Therapy Lecture, which was this year delivered by
Professor Srinivasan Chandrasegaran from the John Hopkins University in
Baltimore, USA. He is the founding father of the highly promising Zinc
Finger Nuclease (ZFN) technology and gave an excellent talk taking the
audience on a journey from the very early days of his discovery through to
potential future applications such as gene therapies for X-SCID and HIV.

This plenary lecture was
followed by a short talk from Dr. Sundar Durai from Pondicherry University
in India, who continued in the ZFN vein by presenting his work on systems
for the high-throughput selection of functional Zinc Finger Proteins
(ZFPs), which can then be used for the generation of novel ZFNs.

The second short talk was
given by Dr. Karoline Lipnik from the University of Veterinary Medicine in
Vienna, Austria, who shared her latest findings on the novel anti-tumour
effects of the human guanylate binding protein (GBP)-1.

This was then followed by the
really stimulating plenary lecture of Stefano Ferrari from the Veneto Eye
Bank Foundation in Venice, Italy, which demonstrated the power of stem
cells to regererated skin and eye injuries, and how a combination of the
advances in tissue engineering, stem cell technology and the application
of gene therapy to keratinocyte stem cells could produce a future therapy
for Epidermolysis Bullosa (EB).

The session was wrapped up by
a short talk from another homegrown “Nachwuchsforscher”, Irene
Pfaffenzeller from the University of Natural Resources and Applied Life
Sciences (BOKU) in Vienna, Austria, who shared the insights which she has
gained from her work on the development of antibiotic-free plasmid
production techniques, which could have far-reaching implications for gene
therapy using non-viral delivery of the therapeutic gene.

London, UK, 1 September 2006 -
Ark Therapeutics Group plc ('Ark' or the 'Company') today announces that
it has filed its response to the first series of questions raised by the
EMEA's scientific committee as part of the marketing authorisation
application (MAA) review process for Cerepro(TM), its novel gene-based
medicine for the treatment of operable high grade glioma (brain cancer).
Ark's response has been filed in accordance with the standard procedure
and time frame. The application for marketing approval was submitted by
Ark in the second half of last year and, following validation of the
submission by the EMEA, was accepted for review in October 2005.

To facilitate the response,
Ark's Finnish manufacturing facility has manufactured the necessary
'conformity' batches of Cerepro(TM) to commercial supply specifications.
The Phase II Cerepro(TM) study, which forms the main clinical evidence in
the submission, has also been subject to a GCP inspection as a specific
part of the MAA review process. In addition, Ark's headquarters has
satisfactorily completed a full good clinical practice ('GCP') system
inspection under the new EU pharmaceutical regulations.

Cerepro(TM) has completed
three clinical studies during its development to date: a Phase I study
establishing safety and posology (dosing and method of administration) and
two safety and efficacy studies. Cerepro(TM) treatment produced an average
extension of 7.5 months of life, almost doubling survival time in a
disease where most patients will only live for around eight months.

Cerepro(TM) has Orphan Drug
Status in Europe and the USA and is the first gene medicine in the world
(1) to undergo a formal MAA review.

Dr Nigel Parker, CEO of Ark,
commented: 'This review is significant because it gives clarity to the
regulatory requirements and standards that need to be met for gene-based
medicines, a new and exciting class of biological drugs in which Ark is
rapidly becoming recognised as a world leader. We continue to make
significant advances with Cerepro(TM) and look forward to providing
further updates on its overall progress in due course.'

Notes (1) ex-China

Life
Sciences 2006, Salzburg, September 25th- 27th

The ANGT is
again teaming up with the other Austrian life-sciences based societies
(ÖGBM, ÖGGGT and ÖGBT) to take part in the 2006 Life Sciences meeting,
which will be held at the University of Salzburg from the 25th to the 27th
of September. Invited speakers working in the field of gene therapy will
include Srinivasan Chandrasegaran (USA) and Michele De Luca (Italy). This
meeting will also provide Austrian scientists with the chance to present
their work , both in oral and poster presentation formats. Abstracts can
be submitted until the 10th of July, and registration for the meeting at a
reduced fee is possible until August 28th. More information can be found
on the meeting homepage using the following link:
http://www.ogbm.org/Jahrestagung.

The
results of a clinical trial published

The results
of a clinical trial published in the April edition of Nature Medicine
provides a novel insight into the role of retroviral insertional
mutagenesis in gene therapy. Until now, the activation of non-target genes
due to the random nature of integration has always been viewed as an
unavoidable and purely negative side effect of using retroviruses as gene
therapy vectors. This new study, which has apparently cured two adult men
from the rare immunodeficiency, chronic granulomatous disease (CGD),
however, indicates that the serendipitous activation of genes that
promoted proliferation and differentiation of the treated cells played an
important role in the success of the trial. The
original paper can be downloaded here , and an editorial on the
subject published in the same journal
can be
downloaded here.

Gene
therapy and oncolytic viral therapy products approved in China

The Chinese State Food and Drug Administration (SFDA) has approved H101,
an oncolytic adenovirus, to be used in combination with chemotherapy as a
treatment for patients with late stage refractory Nasopharyngeal cancer, a
type of head and neck cancer prevalent in China. This marks the first
oncolytic viral therapy approved by any regulatory agency in the world.

An editorial on this subject from the Feb 2006 issue of "Molecular
Therapy" can be viewed here.

This came hot on the heels of the approval by the SFDA of Gendicine, an
adenoviral vector expressing the wild-type p53 gene for the treatment of
head and neck squamous cell carcinoma, which is the first ever
commercially approved gene therapy product worldwide.